The monoclonal anti-CD20 antibody rituximab exerts its antitumor activity through a variety of mechanisms, including acting against the cellular defects in apoptosis that give rise to B-chronic lymphocytic leukemia (B-CLL). Phase II clinical studies demonstrated that rituximab, given weekly as a single agent, exhibits significantly less activity in B-CLL than in indolent B-cell lymphomas. Dose escalation, achieved by a thrice-weekly dosing schedule, is necessary for rituximab to effect significant clinical activity as a single agent. A multicenter, prospective, randomized trial demonstrated that concurrent administration with fludarabine improves the complete response (CR) rate. Ongoing clinical studies are examining the use of rituximab in other combination regimens, including FCR (fludarabine, cyclophosphamide, and rituximab), which has shown great promise in a single-center phase II trial. B-CLL patients may experience more infusion toxicity, including tumor lysis syndrome, to rituximab than patients with lymphoma. However, such infusion toxicity is minimized with appropriate premedication and a stepped up dosing schedule, allowing safe and effective use of rituximab in this disease.